Prostate cancer is one of the most commonly diagnosed cancers in men in the United States and a major cause of cancer morbidity and mortality. The Johns Hopkins Prostate Cancer SPORE is focused on reducing prostate cancer incidence and mortality by translating new laboratory research discoveries into improvements in prostate cancer screening, detection, diagnosis, prevention, and treatment. Thus far, new prostate cancer biomarkers, inherited prostate cancer susceptibility genes, new approaches to prostate cancer immunotherapy, prostate-specific antigen-selective replication-restricted cytolytic adenoviruses, endothelin A receptor antagonists, prostate cancer-specific pro-drugs, and dietary approaches to prostate cancer prevention have all been introduced into clinical trials or population validation studies. This competitive renewal proposal contains six new Translational Research Projects, three Core Resources, two Career Development Projects, and two Developmental Research Projects. Research Project #1 aims to combine aptamer-targeted radiosensitizing interfering RNAs and radiation therapy, Project #2 considers the contributions of prostate-specific antigen itself to prostate cancer progression, Project #3 tests the enhancement of prostate cancer immunotherapy achievable with antibodies against auto-immune checkpoint regulators, Project #4 targets the development of histone deacetylase inhibitors as anti-angiogenic agents for prostate cancer, Project #5 pursues the discovery and validation of epigenetic biomarkers for prostate cancer progression, and Project #6 drives the development of new serum biomarkers for prostate cancer. Each of the Projects directs new scientific findings or insights toward human clinical trials or to population studies; each also features Co-Principal Investigators managing effective multidisciplinary translational research teams. The Research Projects are supported by an Administrative Core (A), which also manages inter-SPORE collaborations, a Tissue Archive Core (B), and a Biostatistics and Epidemiology Core (C).